Febrile neutropenia is the most common life-threatening complication of cancer therapy.[1]Jairam V, Lee V, Park HS, et al. Treatment-related complications of systemic therapy and radiotherapy. JAMA Oncol. 2019 Jul 1;5(7):1028-35.
https://jamanetwork.com/journals/jamaoncology/fullarticle/2729685
http://www.ncbi.nlm.nih.gov/pubmed/30946433?tool=bestpractice.com
If not treated in the first 48 hours, mortality approaches 50%.[87]Bodey GP, Jadeja L, Elting L. Pseudomonas bacteremia. Retrospective analysis of 410 episodes. Arch Intern Med. 1985 Sep;145(9):1621-9.
http://www.ncbi.nlm.nih.gov/pubmed/3927867?tool=bestpractice.com
It is therefore an oncological emergency.
Prompt administration of appropriate empirical antibiotics is associated with marked decrease in mortality.[17]Kuderer NM, Dale DC, Crawford J, et al. Mortality, morbidity, and cost associated with febrile neutropenia in adult cancer patients. Cancer. 2006 May 15;106(10):2258-66.
https://onlinelibrary.wiley.com/doi/full/10.1002/cncr.21847
http://www.ncbi.nlm.nih.gov/pubmed/16575919?tool=bestpractice.com
Delaying administration of empirical antibiotics may lead to worse outcomes (e.g., serious medical complication, increased admission to intensive care unit, sepsis).[88]Koenig C, Schneider C, Morgan JE, et al. Association of time to antibiotics and clinical outcomes in patients with fever and neutropenia during chemotherapy for cancer: a systematic review. Support Care Cancer. 2020 Mar;28(3):1369-83.
http://www.ncbi.nlm.nih.gov/pubmed/31264188?tool=bestpractice.com
A microbiological diagnosis is not made in the majority of patients with febrile neutropenia.[20]Klastersky J, de Naurois J, Rolston K, et al. Management of febrile neutropaenia: ESMO Clinical Practice Guidelines. Ann Oncol. 2016 Sep;27(5 suppl):v111-8.
https://www.annalsofoncology.org/article/S0923-7534(19)31643-6/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/27664247?tool=bestpractice.com
[26]Sipsas NV, Bodey GP, Kontoyiannis DP. Perspectives for the management of febrile neutropenic patients with cancer in the 21st century. Cancer. 2005 Mar 15;103(6):1103-13.
https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/cncr.20890
http://www.ncbi.nlm.nih.gov/pubmed/15666328?tool=bestpractice.com
The likely organism can, however, be suspected based on:[4]National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: prevention and treatment of cancer-related infections [internet publication].
https://www.nccn.org/guidelines/category_3
Site of infection
Underlying malignancy and associated immunological impairment
Type of chemotherapy
Severity and duration of neutropenia
Presence of mucositis
Predominant pathogens at the healthcare facility in which the patient is being treated
It is critical that patients are managed according to local healthcare institution algorithms and guidelines that have been developed based on knowledge of local and regional antibiotic susceptibility patterns [antibiograms]).
Patient-specific management should be informed by individual patient factors, including any prior history of antibiotic-resistant infection and allergy history.
Initial management
Most guidelines recommend administration of the first dose of empirical antibiotics as soon as possible (within 60 minutes of presentation) for a patient with neutropenia with fever (regardless of risk status and intended site of care, inpatient or outpatient).[3]Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2011 Feb 15;52(4):e56-93.
https://academic.oup.com/cid/article/52/4/e56/382256
http://www.ncbi.nlm.nih.gov/pubmed/21258094?tool=bestpractice.com
[20]Klastersky J, de Naurois J, Rolston K, et al. Management of febrile neutropaenia: ESMO Clinical Practice Guidelines. Ann Oncol. 2016 Sep;27(5 suppl):v111-8.
https://www.annalsofoncology.org/article/S0923-7534(19)31643-6/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/27664247?tool=bestpractice.com
[44]Taplitz RA, Kennedy EB, Bow EJ, et al. Antimicrobial prophylaxis for adult patients with cancer-related immunosuppression: ASCO and IDSA clinical practice guideline update. J Clin Oncol. 2018 Oct;36(30):3043-54.
http://ascopubs.org/doi/full/10.1200/JCO.18.00374
http://www.ncbi.nlm.nih.gov/pubmed/30179565?tool=bestpractice.com
Obtain blood cultures before administration of empirical antibiotics to increase likelihood of pathogen detection. These measures enable an initial evaluation (history, physical examination, laboratory investigations) and risk assessment to be performed without undue delay in therapy.
Risk assessment
Several validated risk assessment tools (e.g., Talcott system; Multinational Association of Supportive Care in Cancer [MASCC] score; and Clinical Index of Stable Febrile Neutropenia [CISNE] score) are available to help risk-stratify patients presenting with febrile neutropenia. See Criteria section.
While these tools may help to inform decisions regarding the optimal venue of care for a particular patient (i.e., inpatient or outpatient), they are not surrogates for clinical decision-making.
Patients are typically managed based on whether they are at high risk or low risk for complications or death.
High-risk patients include those who have any of the following:[4]National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: prevention and treatment of cancer-related infections [internet publication].
https://www.nccn.org/guidelines/category_3
[75]Taplitz RA, Kennedy EB, Bow EJ, et al. Outpatient management of fever and neutropenia in adults treated for malignancy: American Society of Clinical Oncology and Infectious Diseases Society of America clinical practice guideline update. J Clin Oncol. 2018 Feb 20;36(14):1443-53.
http://ascopubs.org/doi/full/10.1200/JCO.2017.77.6211
http://www.ncbi.nlm.nih.gov/pubmed/29461916?tool=bestpractice.com
Talcott system group I to III; MASCC risk score <21; or CISNE ≥3
Inpatient status at the time of fever onset
Significant medical comorbidities or clinically unstable
Allogeneic haematopoietic cell transplantation
Anticipated prolonged severe neutropenia (absolute neutrophil count [ANC] ≤100 cells/microlitre and duration ≥7 days)
Hepatic or renal insufficiency
Uncontrolled or progressive cancer
Pneumonia or other complex infection
Use of certain immune and/or targeted treatments (e.g., phosphoinositide 3-kinase [PI3K] inhibitors)
Severe mucositis (grade 3 to 4).
Low-risk patients include those with no high-risk factors and most of the following:[4]National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: prevention and treatment of cancer-related infections [internet publication].
https://www.nccn.org/guidelines/category_3
[75]Taplitz RA, Kennedy EB, Bow EJ, et al. Outpatient management of fever and neutropenia in adults treated for malignancy: American Society of Clinical Oncology and Infectious Diseases Society of America clinical practice guideline update. J Clin Oncol. 2018 Feb 20;36(14):1443-53.
http://ascopubs.org/doi/full/10.1200/JCO.2017.77.6211
http://www.ncbi.nlm.nih.gov/pubmed/29461916?tool=bestpractice.com
[89]Monuszko KA, Albright B, Katherine Montes De Oca M, et al. Evaluation of the clinical index of stable febrile neutropenia risk stratification system for management of febrile neutropenia in gynecologic oncology patients. Gynecol Oncol Rep. 2021 Aug;37:100853.
https://pmc.ncbi.nlm.nih.gov/articles/PMC8414105
http://www.ncbi.nlm.nih.gov/pubmed/34504931?tool=bestpractice.com
Talcott system group IV; MASCC score ≥21; or CISNE score 0*
Outpatient status at the time of fever onset
No associated acute comorbid illness, independently indicating inpatient treatment or close observation
Anticipated short duration of severe neutropenia (ANC ≤100 cells/microlitre for <7 days)
Good performance status (Eastern Cooperative Oncology Group performance status [ECOG PS] 0-1)
No hepatic or renal insufficiency
*National Comprehensive Cancer Network guidelines consider CISNE <3 to be low risk at the initial risk assessment of patients with febrile neutropenia.
Inpatient versus outpatient treatment
Patients with febrile neutropenia who are assessed as high risk should be hospitalised and undergo inpatient treatment.[4]National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: prevention and treatment of cancer-related infections [internet publication].
https://www.nccn.org/guidelines/category_3
[75]Taplitz RA, Kennedy EB, Bow EJ, et al. Outpatient management of fever and neutropenia in adults treated for malignancy: American Society of Clinical Oncology and Infectious Diseases Society of America clinical practice guideline update. J Clin Oncol. 2018 Feb 20;36(14):1443-53.
http://ascopubs.org/doi/full/10.1200/JCO.2017.77.6211
http://www.ncbi.nlm.nih.gov/pubmed/29461916?tool=bestpractice.com
Patients who are assessed as low risk can be considered for outpatient management.[4]National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: prevention and treatment of cancer-related infections [internet publication].
https://www.nccn.org/guidelines/category_3
[75]Taplitz RA, Kennedy EB, Bow EJ, et al. Outpatient management of fever and neutropenia in adults treated for malignancy: American Society of Clinical Oncology and Infectious Diseases Society of America clinical practice guideline update. J Clin Oncol. 2018 Feb 20;36(14):1443-53.
http://ascopubs.org/doi/full/10.1200/JCO.2017.77.6211
http://www.ncbi.nlm.nih.gov/pubmed/29461916?tool=bestpractice.com
Patients require a thorough evaluation and close observation for ≥4 hours before being considered for outpatient management.[75]Taplitz RA, Kennedy EB, Bow EJ, et al. Outpatient management of fever and neutropenia in adults treated for malignancy: American Society of Clinical Oncology and Infectious Diseases Society of America clinical practice guideline update. J Clin Oncol. 2018 Feb 20;36(14):1443-53.
http://ascopubs.org/doi/full/10.1200/JCO.2017.77.6211
http://www.ncbi.nlm.nih.gov/pubmed/29461916?tool=bestpractice.com
Low-risk patients who may be suitable for outpatient management include those with:[4]National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: prevention and treatment of cancer-related infections [internet publication].
https://www.nccn.org/guidelines/category_3
[75]Taplitz RA, Kennedy EB, Bow EJ, et al. Outpatient management of fever and neutropenia in adults treated for malignancy: American Society of Clinical Oncology and Infectious Diseases Society of America clinical practice guideline update. J Clin Oncol. 2018 Feb 20;36(14):1443-53.
http://ascopubs.org/doi/full/10.1200/JCO.2017.77.6211
http://www.ncbi.nlm.nih.gov/pubmed/29461916?tool=bestpractice.com
stable vital signs,
non-critical laboratory results,
appropriate social care and home therapy arrangements (including access to a telephone and emergency facilities, and residing within 1 hour of a medical centre), and
ability to comply with and tolerate oral antibiotic therapy.
Several meta-analyses have found outpatient treatment to be a safe and effective alternative to inpatient management for low-risk patients, with no difference in treatment failure and death rates.[90]Teuffel O, Ethier MC, Alibhai SM, et al. Outpatient management of cancer patients with febrile neutropenia: a systematic review and meta-analysis. Ann Oncol. 2011 Nov;22(11):2358-65.
https://www.annalsofoncology.org/article/S0923-7534(19)37696-3/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/21363878?tool=bestpractice.com
[91]Carstensen M, Sørensen JB. Outpatient management of febrile neutropenia: time to revise the present treatment strategy. J Support Oncol. 2008 May-Jun;6(5):199-208.
http://www.ncbi.nlm.nih.gov/pubmed/18551855?tool=bestpractice.com
[92]Rivas-Ruiz R, Villasis-Keever M, Miranda-Novales G, et al. Outpatient treatment for people with cancer who develop a low-risk febrile neutropaenic event. Cochrane Database Syst Rev. 2019 Mar 19;(3):CD009031.
https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD009031.pub2/full
http://www.ncbi.nlm.nih.gov/pubmed/30887505?tool=bestpractice.com
However, in one meta-analysis, ANC <100 cells/microlitre was identified as a potential predictor of outpatient treatment failure.[91]Carstensen M, Sørensen JB. Outpatient management of febrile neutropenia: time to revise the present treatment strategy. J Support Oncol. 2008 May-Jun;6(5):199-208.
http://www.ncbi.nlm.nih.gov/pubmed/18551855?tool=bestpractice.com
Empirical antibiotics for high-risk patients
High-risk patients should be treated with empirical broad-spectrum antibiotics and hospitalised for further management.[4]National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: prevention and treatment of cancer-related infections [internet publication].
https://www.nccn.org/guidelines/category_3
[75]Taplitz RA, Kennedy EB, Bow EJ, et al. Outpatient management of fever and neutropenia in adults treated for malignancy: American Society of Clinical Oncology and Infectious Diseases Society of America clinical practice guideline update. J Clin Oncol. 2018 Feb 20;36(14):1443-53.
http://ascopubs.org/doi/full/10.1200/JCO.2017.77.6211
http://www.ncbi.nlm.nih.gov/pubmed/29461916?tool=bestpractice.com
The choice of antibiotic regimen should be based on coverage of the most likely pathogens and local susceptibility patterns (as per local healthcare institution algorithms and guidelines), as well as patient-specific factors (e.g., prior history of antibiotic-resistant infection and allergy history).
Antibiotic monotherapy
Empirical antibiotic monotherapy with a beta-lactam (e.g., cefepime, piperacillin/tazobactam, imipenem/cilastatin, or meropenem) is typically recommended for hospitalised patients with febrile neutropenia.[4]National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: prevention and treatment of cancer-related infections [internet publication].
https://www.nccn.org/guidelines/category_3
[20]Klastersky J, de Naurois J, Rolston K, et al. Management of febrile neutropaenia: ESMO Clinical Practice Guidelines. Ann Oncol. 2016 Sep;27(5 suppl):v111-8.
https://www.annalsofoncology.org/article/S0923-7534(19)31643-6/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/27664247?tool=bestpractice.com
[75]Taplitz RA, Kennedy EB, Bow EJ, et al. Outpatient management of fever and neutropenia in adults treated for malignancy: American Society of Clinical Oncology and Infectious Diseases Society of America clinical practice guideline update. J Clin Oncol. 2018 Feb 20;36(14):1443-53.
http://ascopubs.org/doi/full/10.1200/JCO.2017.77.6211
http://www.ncbi.nlm.nih.gov/pubmed/29461916?tool=bestpractice.com
One Cochrane review reported lower risk of mortality, adverse events, and fungal superinfections in patients with febrile neutropenia treated with beta-lactam monotherapy compared with beta-lactam plus an aminoglycoside.[93]Paul M, Dickstein Y, Schlesinger A, et al. Beta-lactam versus beta-lactam-aminoglycoside combination therapy in cancer patients with neutropenia. Cochrane Database Syst Rev. 2013 Jun 29;(6):CD003038.
https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD003038.pub2/full
http://www.ncbi.nlm.nih.gov/pubmed/23813455?tool=bestpractice.com
In situations where anaerobic bacteria are likely to play a role, it would be appropriate to use piperacillin/tazobactam monotherapy as a first-line option, or combine metronidazole with cefepime, or use a carbapenem (meropenem or imipenem/cilastatin).[3]Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2011 Feb 15;52(4):e56-93.
https://academic.oup.com/cid/article/52/4/e56/382256
http://www.ncbi.nlm.nih.gov/pubmed/21258094?tool=bestpractice.com
Piperacillin/tazobactam monotherapy is a reasonable option in settings where resistance (e.g., extended-spectrum beta-lactamase [ESBL]-producing organisms) is not prevalent, based on local institutional bacterial susceptibilities.[4]National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: prevention and treatment of cancer-related infections [internet publication].
https://www.nccn.org/guidelines/category_3
Piperacillin/tazobactam has been shown to be non-inferior to cefepime and ceftazidime in randomised clinical trials.[94]Harter C, Schulze B, Goldschmidt H, et al. Piperacillin/tazobactam vs ceftazidime in the treatment of neutropenic fever in patients with acute leukemia or following autologous peripheral blood stem cell transplantation: a prospective randomized trial. Bone Marrow Transplant. 2006 Feb;37(4):373-9.
http://www.ncbi.nlm.nih.gov/pubmed/16400334?tool=bestpractice.com
[95]Bow EJ, Rotstein C, Noskin GA, et al. A randomized, open-label, multicenter comparative study of the efficacy and safety of piperacillin-tazobactam and cefepime for the empirical treatment of febrile neutropenic episodes in patients with hematologic malignancies. Clin Infect Dis. 2006 Aug 15;43(4):447-59.
http://www.ncbi.nlm.nih.gov/pubmed/16838234?tool=bestpractice.com
[96]Bucaneve G, Micozzi A, Picardi M, et al. Results of a multicenter, controlled, randomized clinical trial evaluating the combination of piperacillin/tazobactam and tigecycline in high-risk hematologic patients with cancer with febrile neutropenia. J Clin Oncol. 2014 May 10;32(14):1463-71.
http://www.ncbi.nlm.nih.gov/pubmed/24733807?tool=bestpractice.com
Extended infusion of piperacillin/tazobactam has been found to be associated with superior treatment outcomes compared with bolus infusion in high-risk patients.[97]Ram R, Halavy Y, Amit O, et al. Extended vs bolus infusion of broad-spectrum β-lactams for febrile neutropenia: an unblinded, randomized trial. Clin Infect Dis. 2018 Sep 28;67(8):1153-60.
http://www.ncbi.nlm.nih.gov/pubmed/29608680?tool=bestpractice.com
Imipenem/cilastatin or meropenem may be preferred if ESBL-producing organisms are prevalent (based on local institutional bacterial susceptibilities).[4]National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: prevention and treatment of cancer-related infections [internet publication].
https://www.nccn.org/guidelines/category_3
[98]Tamma PD, Heil EL, Justo JA, et al. Infectious Diseases Society of America 2024 guidance on the treatment of antimicrobial-resistant gram-negative infections. Clin Infect Dis. 7 Aug 2024 [Epub ahead of print].
http://www.ncbi.nlm.nih.gov/pubmed/39108079?tool=bestpractice.com
Antibiotic combination therapy
Combining a beta-lactam antibiotic with an aminoglycoside (e.g., tobramycin) could be considered (although not routinely recommended) if antibiotic resistance is suspected, with early discontinuation of the aminoglycoside if cultures do not reveal evidence of a drug-resistant organism.[4]National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: prevention and treatment of cancer-related infections [internet publication].
https://www.nccn.org/guidelines/category_3
[75]Taplitz RA, Kennedy EB, Bow EJ, et al. Outpatient management of fever and neutropenia in adults treated for malignancy: American Society of Clinical Oncology and Infectious Diseases Society of America clinical practice guideline update. J Clin Oncol. 2018 Feb 20;36(14):1443-53.
http://ascopubs.org/doi/full/10.1200/JCO.2017.77.6211
http://www.ncbi.nlm.nih.gov/pubmed/29461916?tool=bestpractice.com
Combining a beta-lactam antibiotic with an aminoglycoside (either tobramycin or amikacin, but not gentamicin) may be preferable in patients with Pseudomonas aeruginosa sepsis, while awaiting susceptibility data, given the often multidrug resistance nature of this organism.[20]Klastersky J, de Naurois J, Rolston K, et al. Management of febrile neutropaenia: ESMO Clinical Practice Guidelines. Ann Oncol. 2016 Sep;27(5 suppl):v111-8.
https://www.annalsofoncology.org/article/S0923-7534(19)31643-6/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/27664247?tool=bestpractice.com
[99]Clinical and Laboratory Standards Institute. AST news update June 2023: new! CLSI M100-Ed33: updated aminoglycoside breakpoints for enterobacterales and Pseudomonas aeruginosa. Jun 2023 [internet publication].
https://clsi.org/about/blog/ast-news-update-june-2023-new-clsi-m100-ed33-updated-aminoglycoside-breakpoints-for-enterobacterales-and-pseudomonas-aeruginosa
At institutions with a high prevalence of multidrug-resistant gram-negative bacilli, combining piperacillin/tazobactam with tigecycline may be an option.[96]Bucaneve G, Micozzi A, Picardi M, et al. Results of a multicenter, controlled, randomized clinical trial evaluating the combination of piperacillin/tazobactam and tigecycline in high-risk hematologic patients with cancer with febrile neutropenia. J Clin Oncol. 2014 May 10;32(14):1463-71.
http://www.ncbi.nlm.nih.gov/pubmed/24733807?tool=bestpractice.com
One randomised trial found this combination to be safe, well tolerated, and more effective (as measured by resolution of fever without alterations in antibiotics) than piperacillin/tazobactam monotherapy in patients with febrile neutropenia with high-risk haematological malignancies.[96]Bucaneve G, Micozzi A, Picardi M, et al. Results of a multicenter, controlled, randomized clinical trial evaluating the combination of piperacillin/tazobactam and tigecycline in high-risk hematologic patients with cancer with febrile neutropenia. J Clin Oncol. 2014 May 10;32(14):1463-71.
http://www.ncbi.nlm.nih.gov/pubmed/24733807?tool=bestpractice.com
Mortality was similar for combination therapy and monotherapy.
Indications for empirical extended-spectrum gram-positive coverage
Use of empirical vancomycin (or other extended gram-positive agents, e.g., linezolid, tedizolid, or daptomycin) is not routinely recommended for patients with febrile neutropenia, but may be considered in specific situations where risk of serious gram-positive infection (e.g., MRSA) is high, including suspected catheter-related infection, skin or soft-tissue infection, pneumonia, or haemodynamic instability.[3]Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2011 Feb 15;52(4):e56-93.
https://academic.oup.com/cid/article/52/4/e56/382256
http://www.ncbi.nlm.nih.gov/pubmed/21258094?tool=bestpractice.com
[4]National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: prevention and treatment of cancer-related infections [internet publication].
https://www.nccn.org/guidelines/category_3
[20]Klastersky J, de Naurois J, Rolston K, et al. Management of febrile neutropaenia: ESMO Clinical Practice Guidelines. Ann Oncol. 2016 Sep;27(5 suppl):v111-8.
https://www.annalsofoncology.org/article/S0923-7534(19)31643-6/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/27664247?tool=bestpractice.com
[75]Taplitz RA, Kennedy EB, Bow EJ, et al. Outpatient management of fever and neutropenia in adults treated for malignancy: American Society of Clinical Oncology and Infectious Diseases Society of America clinical practice guideline update. J Clin Oncol. 2018 Feb 20;36(14):1443-53.
http://ascopubs.org/doi/full/10.1200/JCO.2017.77.6211
http://www.ncbi.nlm.nih.gov/pubmed/29461916?tool=bestpractice.com
[100]Beyar-Katz O, Dickstein Y, Borok S, et al. Empirical antibiotics targeting gram-positive bacteria for the treatment of febrile neutropenic patients with cancer. Cochrane Database Syst Rev. 2017 Jun 3;(6):CD003914.
https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD003914.pub4/full
http://www.ncbi.nlm.nih.gov/pubmed/28577308?tool=bestpractice.com
The presence of a central venous catheter alone in a patient with febrile neutropenia is not an indication for empirical vancomycin. The addition of vancomycin to first-line empirical monotherapy in a persistently febrile patient is not advised.[100]Beyar-Katz O, Dickstein Y, Borok S, et al. Empirical antibiotics targeting gram-positive bacteria for the treatment of febrile neutropenic patients with cancer. Cochrane Database Syst Rev. 2017 Jun 3;(6):CD003914.
https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD003914.pub4/full
http://www.ncbi.nlm.nih.gov/pubmed/28577308?tool=bestpractice.com
[101]Cometta A, Kern WV, De Bock R, et al. Vancomycin versus placebo for treating persistent fever in patients with neutropenic cancer receiving piperacillin-tazobactam monotherapy. Clin Infect Dis. 2003 Aug 1;37(3):382-9.
https://academic.oup.com/cid/article/37/3/382/436264
http://www.ncbi.nlm.nih.gov/pubmed/12884163?tool=bestpractice.com
Judicious use of vancomycin is warranted due to the increasing prevalence of antibiotic-resistant gram-positive organisms (e.g., vancomycin-resistant enterococci) and the potential for nephrotoxicity associated with this agent.[102]Tong SY, Davis JS, Eichenberger E, et al. Staphylococcus aureus infections: epidemiology, pathophysiology, clinical manifestations, and management. Clin Microbiol Rev. 2015 Jul;28(3):603-61.
https://journals.asm.org/doi/10.1128/CMR.00134-14
http://www.ncbi.nlm.nih.gov/pubmed/26016486?tool=bestpractice.com
[103]Hospital Infection Control Practices Advisory Committee. Recommendations for preventing the spread of vancomycin resistance: recommendations of the Hospital Infection Control Practices Advisory Committee (HICPAC). Am J Infect Control. 1995 Apr;23(2):87-94.
http://www.ncbi.nlm.nih.gov/pubmed/7639408?tool=bestpractice.com
Linezolid, tedizolid, or daptomycin can be used as an alternative in patients who are intolerant of vancomycin, and should be considered for patients with sepsis and known colonisation or prior infection with vancomycin-resistant enterococci.[104]Jaksic B, Martinelli G, Perez-Oteyza J, et al. Efficacy and safety of linezolid compared with vancomycin in a randomized, double-blind study of febrile neutropenic patients with cancer. Clin Infect Dis. 2006 Mar 1;42(5):597-607.
http://www.ncbi.nlm.nih.gov/pubmed/16447103?tool=bestpractice.com
Daptomycin should not be used in patients with pneumonia as it is inactivated by pulmonary surfactant.
Use of empirical vancomycin (or other gram-positive antibiotics) should be reassessed following 2-3 days of treatment, and discontinued if a gram-positive pathogen is not identified on blood cultures.[4]National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: prevention and treatment of cancer-related infections [internet publication].
https://www.nccn.org/guidelines/category_3
Empirical antibiotics for low-risk patients
Low-risk patients who are suitable for outpatient management can receive oral therapy with a fluoroquinolone (e.g., ciprofloxacin, levofloxacin) plus amoxicillin/clavulanate (or clindamycin if the patient is allergic to penicillin) if fluoroquinolone prophylaxis was not used before fever onset, and provided the patient does not have a history of infection or colonisation with a fluoroquinolone-resistant organism.[75]Taplitz RA, Kennedy EB, Bow EJ, et al. Outpatient management of fever and neutropenia in adults treated for malignancy: American Society of Clinical Oncology and Infectious Diseases Society of America clinical practice guideline update. J Clin Oncol. 2018 Feb 20;36(14):1443-53.
http://ascopubs.org/doi/full/10.1200/JCO.2017.77.6211
http://www.ncbi.nlm.nih.gov/pubmed/29461916?tool=bestpractice.com
[105]Escalante CP, Weiser MA, Manzullo E, et al. Outcomes of treatment pathways in outpatient treatment of low risk febrile neutropenic cancer patients. Support Care Cancer. 2004 Sep;12(9):657-62.
http://www.ncbi.nlm.nih.gov/pubmed/15185134?tool=bestpractice.com
Fluoroquinolone monotherapy can also be considered in these patients.[106]Kern WV, Marchetti O, Drgona L, et al. Oral antibiotics for fever in low-risk neutropenic patients with cancer: a double-blind, randomized, multicenter trial comparing single daily moxifloxacin with twice daily ciprofloxacin plus amoxicillin/clavulanic acid combination therapy - EORTC infectious diseases group trial XV. J Clin Oncol. 2013 Mar 20;31(9):1149-56.
http://ascopubs.org/doi/full/10.1200/JCO.2012.45.8109
http://www.ncbi.nlm.nih.gov/pubmed/23358983?tool=bestpractice.com
[107]Rolston KV, Frisbee-Hume SE, Patel S, et al. Oral moxifloxacin for outpatient treatment of low-risk, febrile neutropenic patients. Support Care Cancer. 2010 Jan;18(1):89-94.
http://www.ncbi.nlm.nih.gov/pubmed/19387695?tool=bestpractice.com
Systemic fluoroquinolone antibiotics may cause serious, disabling, and potentially long-lasting or irreversible adverse events. This includes, but is not limited to: tendinopathy/tendon rupture; peripheral neuropathy; arthropathy/arthralgia; aortic aneurysm and dissection; heart valve regurgitation; dysglycaemia; and central nervous system effects including seizures, depression, psychosis, and suicidal thoughts and behaviour.[68]Rusu A, Munteanu AC, Arbănași EM, et al. Overview of side-effects of antibacterial fluoroquinolones: new drugs versus old drugs, a step forward in the safety profile? Pharmaceutics. 2023 Mar 1;15(3):804
https://www.mdpi.com/1999-4923/15/3/804
http://www.ncbi.nlm.nih.gov/pubmed/36986665?tool=bestpractice.com
Prescribing restrictions apply to the use of fluoroquinolones, and these restrictions may vary between countries. In general, fluoroquinolones should be restricted for use in serious, life-threatening bacterial infections only. Some regulatory agencies may also recommend that they must only be used in situations where other antibiotics, that are commonly recommended for the infection, are inappropriate (e.g., resistance, contraindications, treatment failure, unavailability).
Consult your local guidelines and drug information source for more information on suitability, contraindications, and precautions.
Some low-risk patients may be treated with an outpatient parenteral regimen, although there are no clinical trials to support their use.
Hospital admission and inpatient management should be considered if any of the following occur in low-risk patients undergoing outpatient management:[75]Taplitz RA, Kennedy EB, Bow EJ, et al. Outpatient management of fever and neutropenia in adults treated for malignancy: American Society of Clinical Oncology and Infectious Diseases Society of America clinical practice guideline update. J Clin Oncol. 2018 Feb 20;36(14):1443-53.
http://ascopubs.org/doi/full/10.1200/JCO.2017.77.6211
http://www.ncbi.nlm.nih.gov/pubmed/29461916?tool=bestpractice.com
No defervescence after 2-3 days of initial empirical antibiotic therapy
Fever recurrence after a period of defervescence
New signs or symptoms of infection
Use of oral therapy is no longer possible or tolerable
Change in the empirical regimen or an additional antimicrobial drug becomes necessary
Microbiological tests identify species not susceptible to the initial regimen
Treatment duration and de-escalation
Empirical antibiotic treatment (excluding extended-spectrum gram-positive coverage [see above]) is typically continued until neutrophil recovery (i.e., ANC ≥500 cells/microlitre and increasing).[3]Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2011 Feb 15;52(4):e56-93.
https://academic.oup.com/cid/article/52/4/e56/382256
http://www.ncbi.nlm.nih.gov/pubmed/21258094?tool=bestpractice.com
[4]National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: prevention and treatment of cancer-related infections [internet publication].
https://www.nccn.org/guidelines/category_3
Once empirical antibiotics are started, the median time to clinical response is 5-7 days. Antibiotics should not be changed empirically in the face of persistent fever for the first 3-5 days, provided the patient is clinically stable.[108]Elting LS, Rubenstein EB, Rolston K, et al. Time to clinical response: an outcome of antibiotic therapy of febrile neutropenia with implications for quality and cost of care. J Clin Oncol. 2000 Nov 1;18(21):3699-706.
http://www.ncbi.nlm.nih.gov/pubmed/11054443?tool=bestpractice.com
Negative blood cultures and source of infection unidentified
For clinically stable patients with persistent neutropenia who have defervesced (afebrile for at least 48 hours) on empirical broad-spectrum parenteral antibiotics and have negative blood cultures and no identified source of infection, consider:[4]National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: prevention and treatment of cancer-related infections [internet publication].
https://www.nccn.org/guidelines/category_3
antibiotic de-escalation (e.g., to oral fluoroquinolone prophylaxis), or
discontinuation (if use of antibiotic prophylaxis is not standard protocol).
Evidence supporting safe early discontinuation of antibiotic therapy in patients with febrile neutropenia is growing, including in high-risk patients.[109]Le Clech L, Talarmin JP, Couturier MA, et al. Early discontinuation of empirical antibacterial therapy in febrile neutropenia: the ANTIBIOSTOP study. Infect Dis (Lond). 2018 Jul;50(7):539-49.
http://www.ncbi.nlm.nih.gov/pubmed/29451055?tool=bestpractice.com
[110]Van de Wyngaert Z, Berthon C, Debarri H, et al. Discontinuation of antimicrobial therapy in adult neutropenic haematology patients: a prospective cohort. Int J Antimicrob Agents. 2019 Jun;53(6):781-8.
http://www.ncbi.nlm.nih.gov/pubmed/30831232?tool=bestpractice.com
[111]Verlinden A, Jansens H, Goossens H, et al. Safety and efficacy of antibiotic de-escalation and discontinuation in high-risk hematological patients with febrile neutropenia: a single-center experience. Open Forum Infect Dis. 2022 Mar;9(3):ofab624.
https://academic.oup.com/ofid/article/9/3/ofab624/6481743
http://www.ncbi.nlm.nih.gov/pubmed/35146042?tool=bestpractice.com
[112]Averbuch D, Orasch C, Cordonnier C, et al. European guidelines for empirical antibacterial therapy for febrile neutropenic patients in the era of growing resistance: summary of the 2011 4th European Conference on Infections in Leukemia. Haematologica. 2013 Dec;98(12):1826-35.
https://haematologica.org/article/view/6857
http://www.ncbi.nlm.nih.gov/pubmed/24323983?tool=bestpractice.com
[113]Aguilar-Guisado M, Espigado I, Martín-Peña A, et al. Optimisation of empirical antimicrobial therapy in patients with haematological malignancies and febrile neutropenia (How Long study): an open-label, randomised, controlled phase 4 trial. Lancet Haematol. 2017 Dec;4(12):e573-83.
http://www.ncbi.nlm.nih.gov/pubmed/29153975?tool=bestpractice.com
[114]Stern A, Carrara E, Bitterman R, et al. Early discontinuation of antibiotics for febrile neutropenia versus continuation until neutropenia resolution in people with cancer. Cochrane Database Syst Rev. 2019 Jan 3;(1):CD012184.
https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD012184.pub2/full
http://www.ncbi.nlm.nih.gov/pubmed/30605229?tool=bestpractice.com
[115]de Jonge NA, Sikkens JJ, Zweegman S, et al. Short versus extended treatment with a carbapenem in patients with high-risk fever of unknown origin during neutropenia: a non-inferiority, open-label, multicentre, randomised trial. Lancet Haematol. 2022 Aug;9(8):e563-72.
http://www.ncbi.nlm.nih.gov/pubmed/35691326?tool=bestpractice.com
Patients with persistent fever despite neutrophil recovery warrant continued empirical therapy and further diagnostic evaluation.[20]Klastersky J, de Naurois J, Rolston K, et al. Management of febrile neutropaenia: ESMO Clinical Practice Guidelines. Ann Oncol. 2016 Sep;27(5 suppl):v111-8.
https://www.annalsofoncology.org/article/S0923-7534(19)31643-6/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/27664247?tool=bestpractice.com
Microbiologically documented infection
For patients with documented infection, the duration and de-escalation of antibiotic therapy should be individualised based on neutrophil recovery, speed of defervescence, specific pathogen and site of infection, and underlying disease.[4]National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: prevention and treatment of cancer-related infections [internet publication].
https://www.nccn.org/guidelines/category_3
Duration of treatment is typically 5-14 days for bacterial infections of the skin/soft tissue, sinuses, and lungs, and 7-14 days for most bacterial bloodstream infections.[4]National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: prevention and treatment of cancer-related infections [internet publication].
https://www.nccn.org/guidelines/category_3
Catheter removal is recommended in the context of bloodstream infections with Staphylococcus aureus, Pseudomonas aeruginosa, Corynebacterium jeikeium, Candida (or other yeasts), Acinetobacter, Stenotrophomonas maltophilia, Bacillus organisms, moulds, non-tuberculous mycobacteria, vancomycin-resistant enterococci (VRE), or other multidrug-resistant organisms.[4]National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: prevention and treatment of cancer-related infections [internet publication].
https://www.nccn.org/guidelines/category_3
[20]Klastersky J, de Naurois J, Rolston K, et al. Management of febrile neutropaenia: ESMO Clinical Practice Guidelines. Ann Oncol. 2016 Sep;27(5 suppl):v111-8.
https://www.annalsofoncology.org/article/S0923-7534(19)31643-6/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/27664247?tool=bestpractice.com
Catheters should also be removed in patients who have sepsis with a suspected line source; those with persistent bacteraemia despite effective antibiotic therapy; and those with tunnel or port pocket infection.[4]National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: prevention and treatment of cancer-related infections [internet publication].
https://www.nccn.org/guidelines/category_3
[20]Klastersky J, de Naurois J, Rolston K, et al. Management of febrile neutropaenia: ESMO Clinical Practice Guidelines. Ann Oncol. 2016 Sep;27(5 suppl):v111-8.
https://www.annalsofoncology.org/article/S0923-7534(19)31643-6/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/27664247?tool=bestpractice.com
Persistent fever
Patients with persistent fever beyond the first 3-5 days of empirical therapy require additional evaluation (e.g., imaging and microbiological testing) for a possible occult fungal infection, bacterial infection with cryptic foci or resistant organisms, or a viral infection.[3]Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2011 Feb 15;52(4):e56-93.
https://academic.oup.com/cid/article/52/4/e56/382256
http://www.ncbi.nlm.nih.gov/pubmed/21258094?tool=bestpractice.com
If a thorough evaluation for infection is unrevealing in the face of persistent fever despite appropriate empirical therapy, a non-infectious cause for fever (e.g., drug fever, tumour fever, thromboembolism) should be considered.
Low-risk patients with persistent fever despite 2-3 days of empirical outpatient antibiotic therapy should be re-evaluated, with strong consideration for inpatient management.[75]Taplitz RA, Kennedy EB, Bow EJ, et al. Outpatient management of fever and neutropenia in adults treated for malignancy: American Society of Clinical Oncology and Infectious Diseases Society of America clinical practice guideline update. J Clin Oncol. 2018 Feb 20;36(14):1443-53.
http://ascopubs.org/doi/full/10.1200/JCO.2017.77.6211
http://www.ncbi.nlm.nih.gov/pubmed/29461916?tool=bestpractice.com
Empirical antifungal therapy
The addition of empirical mould-active antifungal therapy should be considered for high-risk patients with persistent fever despite ≥4 days of empirical antibiotic therapy.[3]Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2011 Feb 15;52(4):e56-93.
https://academic.oup.com/cid/article/52/4/e56/382256
http://www.ncbi.nlm.nih.gov/pubmed/21258094?tool=bestpractice.com
[4]National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: prevention and treatment of cancer-related infections [internet publication].
https://www.nccn.org/guidelines/category_3
The choice and timing of empirical antifungal therapy is guided by local institutional guidelines, risk for invasive mould infection, prior mould-active antifungal prophylaxis (if received), severity of illness, and specific risk for drug-drug interactions or toxicity in an individual patient.
Colony-stimulating factors (CSFs)
The use of CSFs (i.e., granulocyte colony-stimulating factor [G-CSF] or granulocyte-macrophage colony-stimulating factor [GM-CSF]) for treating patients with febrile neutropenia is controversial.
Limited data suggest a benefit with respect to time to neutrophil recovery, duration of antibiotic therapy, and length of hospitalisation, but no benefit with respect to overall mortality.[45]National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: hematopoietic growth factors [internet publication].
https://www.nccn.org/guidelines/category_3
[116]Mhaskar R, Clark OA, Lyman G, et al. Colony-stimulating factors for chemotherapy-induced febrile neutropenia. Cochrane Database Syst Rev. 2014 Oct 30;(10):CD003039.
https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD003039.pub2/full
http://www.ncbi.nlm.nih.gov/pubmed/25356786?tool=bestpractice.com
As such, the use of empirical CSFs (available as short-acting G-CSF formulations [e.g., filgrastim] or long-acting G-CSF formulations [e.g., pegfilgrastim, eflapegrastim, efbemalenograstim alfa, lipegfilgrastim], or as GM-CSF [e.g., sargramostim]) for treating patients with febrile neutropenia is typically not recommended.[57]Smith TJ, Bohlke K, Lyman GH, et al. Recommendations for the use of WBC growth factors: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2015 Oct 1;33(28):3199-212.
http://ascopubs.org/doi/full/10.1200/JCO.2015.62.3488
http://www.ncbi.nlm.nih.gov/pubmed/26169616?tool=bestpractice.com
Consideration may, however, be given to CSFs in high-risk patients with pneumonia, multiorgan dysfunction (sepsis syndrome), invasive fungal infection, or uncontrolled primary disease; or in patients who are persistently febrile (>10 days), have profound neutropenia (ANC <100 cells/microlitre), are age >65 years, were hospitalised at the time of fever development, or who have had a previous episode of febrile neutropenia.[45]National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: hematopoietic growth factors [internet publication].
https://www.nccn.org/guidelines/category_3
[57]Smith TJ, Bohlke K, Lyman GH, et al. Recommendations for the use of WBC growth factors: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2015 Oct 1;33(28):3199-212.
http://ascopubs.org/doi/full/10.1200/JCO.2015.62.3488
http://www.ncbi.nlm.nih.gov/pubmed/26169616?tool=bestpractice.com
In patients who have received prophylactic G-CSF, National Comprehensive Cancer Network guidelines recommend continuation of G-CSF, unless a long-acting G-CSF was used prophylactically.[45]National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: hematopoietic growth factors [internet publication].
https://www.nccn.org/guidelines/category_3